System and method for cleaning noisy genetic data and determining chromosome copy number

Abstract

Disclosed herein is a system and method for increasing the fidelity of measured genetic data, for making allele calls, and for determining the state of aneuploidy, in one or a small set of cells, or from fragmentary DNA, where a limited quantity of genetic data is available. Poorly or incorrectly measured base pairs, missing alleles and missing regions are reconstructed using expected similarities between the target genome and the genome of genetically related individuals. In accordance with one embodiment, incomplete genetic data from an embryonic cell are reconstructed at a plurality of loci using the more complete genetic data from a larger sample of diploid cells from one or both parents, with or without haploid genetic data from one or both parents. In another embodiment, the chromosome copy number can be determined from the measured genetic data, with or without genetic information from one or both parents.

What is claimed is: 
     
         1 . A method for preparing a preparation of amplified DNA from a biological sample of a first individual useful for measuring DNA from a second individual, the method comprising:
 isolating cell-free DNA from the biological sample, wherein the biological sample comprises DNA from the first individual and DNA from the second individual;   preparing a preparation of amplified DNA by amplifying a plurality of SNP loci from the isolated cell-free DNA or DNA derived therefrom in a single reaction volume;   analyzing the preparation of amplified DNA by high-throughput sequencing to obtain genetic data for the plurality of SNP loci, and measuring DNA from the second individual based on allele frequencies in the genetic data obtained.   
     
     
         2 . The method of  claim 1 , wherein the biological sample is a blood sample. 
     
     
         3 . The method of  claim 1 , wherein the amplifying comprises universal amplification. 
     
     
         4 . The method of  claim 1 , wherein the amplifying comprises targeted amplification. 
     
     
         5 . The method of  claim 1 , wherein the amplifying comprises ligation-mediated PCR. 
     
     
         6 . The method of  claim 1 , wherein the high-throughput sequencing comprises sequencing-by-synthesis. 
     
     
         7 . The method of  claim 1 , wherein the target loci comprise at least 70 SNP loci. 
     
     
         8 . The method of  claim 1 , wherein the confidence that each SNP is correctly called is at least 95%. 
     
     
         9 . The method of  claim 1 , wherein the confidence that each SNP is correctly called is at least 99%. 
     
     
         10 . The method of  claim 1 , further comprising normalizing the genetic data for differences in amplification and/or measurement efficiency between the loci. 
     
     
         11 . A method for preparing a high-throughput sequencing library from a sample comprising DNA from a first individual and a second individual, the method comprising:
 isolating cell-free DNA from a blood sample of the first individual,   amplifying a plurality of SNP loci from the isolated cell-free DNA in a single reaction volume to obtain a preparation of amplification products,   hybridizing a probe at each of the SNP loci of the amplification products, and   using high-throughput sequencing to measure at least 100 SNP loci of the amplification products,   wherein the isolated cell-free DNA comprises DNA from the first individual and DNA from the second individual.   
     
     
         12 . The method of  claim 11 , wherein the amplifying comprises universal amplification. 
     
     
         13 . The method of  claim 11 , wherein the amplifying comprises targeted amplification. 
     
     
         14 . The method of  claim 11 , wherein the amplifying comprises whole genome amplification. 
     
     
         15 . The method of  claim 11 , wherein the amplifying comprises ligation-mediated PCR. 
     
     
         16 . The method of  claim 11 , wherein the high-throughput sequencing comprises sequencing-by-synthesis. 
     
     
         17 . The method of  claim 11 , wherein each probe is arranged in an array. 
     
     
         18 . The method of  claim 11 , wherein each probe is a molecular inversion probe (MIP). 
     
     
         19 . The method of  claim 11 , wherein measuring the at least 100 SNP loci comprises measuring a signal associated with a nucleotide for each of the SNP loci in the amplification products. 
     
     
         20 . The method of  claim 11 , wherein the at least 100 SNP loci are from at least two genes of the DNA from the first individual and DNA from the second individual.